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1.
Am J Physiol Cell Physiol ; 326(4): C1120-C1177, 2024 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-38223926

RESUMEN

Cardiotonic steroids (CTS), used by certain insects, toads, and rats for protection from predators, became, thanks to Withering's trailblazing 1785 monograph, the mainstay of heart failure (HF) therapy. In the 1950s and 1960s, we learned that the CTS receptor was part of the sodium pump (NKA) and that the Na+/Ca2+ exchanger was critical for the acute cardiotonic effect of digoxin- and ouabain-related CTS. This "settled" view was upended by seven revolutionary observations. First, subnanomolar ouabain sometimes stimulates NKA while higher concentrations are invariably inhibitory. Second, endogenous ouabain (EO) was discovered in the human circulation. Third, in the DIG clinical trial, digoxin only marginally improved outcomes in patients with HF. Fourth, cloning of NKA in 1985 revealed multiple NKA α and ß subunit isoforms that, in the rodent, differ in their sensitivities to CTS. Fifth, the NKA is a cation pump and a hormone receptor/signal transducer. EO binding to NKA activates, in a ligand- and cell-specific manner, several protein kinase and Ca2+-dependent signaling cascades that have widespread physiological effects and can contribute to hypertension and HF pathogenesis. Sixth, all CTS are not equivalent, e.g., ouabain induces hypertension in rodents while digoxin is antihypertensinogenic ("biased signaling"). Seventh, most common rodent hypertension models require a highly ouabain-sensitive α2 NKA and the elevated blood pressure is alleviated by EO immunoneutralization. These numerous phenomena are enabled by NKA's intricate structure. We have just begun to understand the endocrine role of the endogenous ligands and the broad impact of the ouabain-binding site on physiology and pathophysiology.


Asunto(s)
Insuficiencia Cardíaca , Hipertensión , Humanos , Ratas , Animales , Ouabaína/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Ligandos , Digoxina/farmacología , Cardiotónicos/farmacología , Hipertensión/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Señalización del Calcio , Sitios de Unión
2.
Am J Physiol Heart Circ Physiol ; 323(6): H1281-H1295, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36367691

RESUMEN

Cloning of the "Na+ pump" (Na+,K+-ATPase or NKA) and identification of a circulating ligand, endogenous ouabain (EO), a cardiotonic steroid (CTS), triggered seminal discoveries regarding EO and its NKA receptor in cardiovascular function and the pathophysiology of heart failure (HF) and hypertension. Cardiotonic digitalis preparations were a preferred treatment for HF for two centuries, but digoxin was only marginally effective in a large clinical trial (1997). This led to diminished digoxin use. Missing from the trial, however, was any consideration that endogenous CTS might influence digitalis' efficacy. Digoxin, at therapeutic concentrations, acutely inhibits NKA but, remarkably, antagonizes ouabain's action. Prolonged treatment with ouabain, but not digoxin, causes hypertension in rodents; in this model, digoxin lowers blood pressure (BP). Furthermore, NKA-bound ouabain and digoxin modulate different protein kinase signaling pathways and have disparate long-term cardiovascular effects. Reports of "brain ouabain" led to the elucidation of a new, slow neuromodulatory pathway in the brain; locally generated EO and the α2 NKA isoform help regulate sympathetic drive to the heart and vasculature. The roles of EO and α2 NKA have been studied by EO assay, ouabain-resistant mutation of α2 NKA, and immunoneutralization of EO with ouabain-binding Fab fragments. The NKA α2 CTS binding site and its endogenous ligand are required for BP elevation in many common hypertension models and full expression of cardiac remodeling and dysfunction following pressure overload or myocardial infarction. Understanding how endogenous CTS impact hypertension and HF pathophysiology and therapy should foster reconsideration of digoxin's therapeutic utility.


Asunto(s)
Glicósidos Cardíacos , Digitalis , Insuficiencia Cardíaca , Hipertensión , Ligandos , Insuficiencia Cardíaca/tratamiento farmacológico , Hipertensión/tratamiento farmacológico
3.
Pharm Biol ; 59(1): 1008-1015, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34362288

RESUMEN

CONTEXT: Cucumber (Cucumis sativus Linn. [Cucurbitaceae]) is widely known for its purgative, antidiabetic, antioxidant, and anticancer therapeutic potential. However, its effect on gastrointestinal (GI) disease is unrecognised. OBJECTIVE: This study investigated the effect of C. sativus fruit extract (CCE) on intestinal chloride secretion, motility, and motor function, and the role of TMEM16A chloride channels. MATERIALS AND METHODS: CCE extracts were obtained from commercially available cucumber. Active fractions were then purified by HPLC and analysed by high resolution mass spectrometry. The effect of CCE on intestinal chloride secretion was investigated in human colonic T84 cells, ex vivo mouse intestinal tissue using an Ussing chamber, and the two-electrode voltage-clamp technique to record calcium sensitive TMEM16A chloride currents in Xenopus laevis oocytes. In vivo, intestinal motility was investigated using the loperamide-induced C57BL/6 constipation mouse model. Ex vivo contractility of mouse colonic smooth muscles was assessed by isometric force measurements. RESULTS: CCE increased the short-circuit current (ΔIsc 34.47 ± µA/cm2) and apical membrane chloride conductance (ΔICl 95 ± 8.1 µA/cm2) in intestinal epithelial cells. The effect was dose-dependent, with an EC50 value of 0.06 µg/mL. CCE stimulated the endogenous TMEM16A-induced Cl- current in Xenopus laevis oocytes. Moreover, CCE increased the contractility of smooth muscle in mouse colonic tissue and enhanced small bowel transit in CCE treated mice compared to loperamide controls. Mass spectrometry suggested a cucurbitacin-like analogue with a mass of 512.07 g/mol underlying the bioactivity of CCE. CONCLUSION: A cucurbitacin-like analog present in CCE activates TMEM16A channels, which may have therapeutic potential in cystic fibrosis and intestinal hypodynamic disorders.


Asunto(s)
Anoctamina-1/metabolismo , Cloruros/metabolismo , Cucumis sativus/química , Intestinos/efectos de los fármacos , Canales Iónicos/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Línea Celular , Estreñimiento/inducido químicamente , Estreñimiento/tratamiento farmacológico , Motilidad Gastrointestinal/efectos de los fármacos , Humanos , Loperamida/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Músculo Liso/efectos de los fármacos , Técnicas de Placa-Clamp , Xenopus laevis
4.
Am J Kidney Dis ; 73(4): 504-512, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30660405

RESUMEN

RATIONALE & OBJECTIVE: Studies of humans and animals have suggested that endogenous ouabain (EO) and related genes are mediators of acute (AKI) and chronic kidney injury. We sought to examine the relationship among EO levels, genetic variants in lanosterol synthase (LSS; an enzyme that catalyzes synthesis of cholesterol, a precursor of EO), and both AKI and chronic kidney injury. STUDY DESIGN: 2 prospective observational cohort studies and a cross-sectional study of kidney tissue. SETTING & PARTICIPANTS: (1) A prospective cohort study of patients undergoing cardiovascular surgery, (2) measurement of EO concentration in kidney tissue removed because of an adjacent tumor, and (3) a prospective cohort study of patients with newly diagnosed essential hypertension. EXPOSURE: Missense variant in LSS (A instead of C allele at rs2254524), which leads to a valine to leucine substitution at amino acid 642. OUTCOMES: Development of postoperative AKI in the cardiovascular surgery cohort, EO concentration in kidney tissue, and estimated glomerular filtration rate (eGFR) reductions in the essential hypertension cohort. ANALYTICAL APPROACH: Logistic regression for analysis of postoperative AKI, analysis of variance for EO concentration in kidney tissue, and generalized linear models for changes in eGFR over time. RESULTS: AKI incidence following cardiovascular surgery was greater among those with the LSS rs2254524 AA genotype (30.7%) than in those with the CC genotype (17.4%; P=0.001). LSS rs2254524 AA kidneys had higher EO concentrations than CC kidneys (2.14±0.29 vs 1.25±0.08ng/g; P<0.001). In the longitudinal study of patients with essential hypertension (median follow-up, 4 years; range, 1-15 years), eGFR decline was greater among the LSS rs2254524 AA genotype group (-4.39±1.18mL/min/1.73m2 per year) than in the AC or CC genotype groups (-1.07±0.55 and -2.00±0.45mL/min/1.73m2 per year respectively; P = 0.03). LIMITATIONS: These associations do not necessarily represent causal relationships; LSS rs2254524 variants may have effects on other steroid hormones. CONCLUSIONS: These findings support the potential value of LSS rs2254524 genotype-based risk stratification to identify patients at high risk for AKI before cardiovascular surgery, as well as predict accelerated eGFR in the setting of hypertension. These findings also suggest that LSS may in part drive EO-mediated kidney damage. EO may represent a new potential therapeutic target for the prevention of AKI and slowing of kidney damage in the setting of hypertension.


Asunto(s)
Lesión Renal Aguda/metabolismo , Transferasas Intramoleculares/metabolismo , Ouabaína/metabolismo , Complicaciones Posoperatorias , Insuficiencia Renal Crónica/metabolismo , Lesión Renal Aguda/etiología , Lesión Renal Aguda/genética , Adolescente , Adulto , Anciano , Procedimientos Quirúrgicos Cardiovasculares/efectos adversos , Estudios Transversales , Femenino , Estudios de Seguimiento , Variación Genética , Humanos , Transferasas Intramoleculares/genética , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Radioinmunoensayo , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/genética , Adulto Joven
5.
J Physiol ; 594(21): 6079-6103, 2016 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-27350568

RESUMEN

Reduced smooth muscle (SM)-specific α2 Na+ pump expression elevates basal blood pressure (BP) and increases BP sensitivity to angiotensin II (Ang II) and dietary NaCl, whilst SM-α2 overexpression lowers basal BP and decreases Ang II/salt sensitivity. Prolonged ouabain infusion induces hypertension in rodents, and ouabain-resistant mutation of the α2 ouabain binding site (α2R/R mice) confers resistance to several forms of hypertension. Pressure overload-induced heart hypertrophy and failure are attenuated in cardio-specific α2 knockout, cardio-specific α2 overexpression and α2R/R mice. We propose a unifying hypothesis that reconciles these apparently disparate findings: brain mechanisms, activated by Ang II and high NaCl, regulate sympathetic drive and a novel neurohumoral pathway mediated by both brain and circulating endogenous ouabain (EO). Circulating EO modulates ouabain-sensitive α2 Na+ pump activity and Ca2+ transporter expression and, via Na+ /Ca2+ exchange, Ca2+ homeostasis. This regulates sensitivity to sympathetic activity, Ca2+ signalling and arterial and cardiac contraction.


Asunto(s)
Sistema Cardiovascular/metabolismo , Hipertensión/metabolismo , Ouabaína/farmacología , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Angiotensinas/metabolismo , Animales , Sitios de Unión , Cardiotónicos/farmacología , Sistema Cardiovascular/efectos de los fármacos , Humanos , Hipertensión/fisiopatología , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , ATPasa Intercambiadora de Sodio-Potasio/química , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/fisiología
7.
J Physiol ; 592(5): 941-69, 2014 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-24344167

RESUMEN

'Classic' cardiotonic steroids (CTSs) such as digoxin and ouabain selectively inhibit Na+, K+ -ATPase (the Na+ pump) and, via Na+ / Ca2+ exchange (NCX), exert cardiotonic and vasotonic effects. CTS action is more complex than previously thought: prolonged subcutaneous administration of ouabain, but not digoxin, induces hypertension, and digoxin antagonizes ouabain's hypertensinogenic effect. We studied the acute interactions between CTSs in two indirect assays of Na+ pump function: myogenic tone (MT) in isolated, pressurized rat mesenteric small arteries, and Ca2+ signalling in primary cultured rat hippocampal neurones. The 'classic' CTSs (0.3-10 nm) behaved as 'agonists': all increased MT70 (MT at 70 mmHg) and augmented glutamate-evoked Ca2+ (Fura-2) signals. We then tested one CTS in the presence of another. Most CTSs could be divided into ouabain-like (ouabagenin, dihydroouabain (DHO), strophanthidin) or digoxin-like CTS (digoxigenin, digitoxin, bufalin). Within each group, the CTSs were synergistic, but ouabain-like and digoxin-like CTSs antagonized one another in both assays: For example, the ouabain-evoked (3 nm) increases in MT70 and neuronal Ca2+ signals were both greatly attenuated by the addition of 10 nm digoxin or 10 nm bufalin, and vice versa. Rostafuroxin (PST2238), a digoxigenin derivative that displaces 3H-ouabain from Na+, K+ -ATPase, and attenuates some forms of hypertension, antagonized the effects of ouabain, but not digoxin. SEA0400, a Na+ / Ca2+ exchanger (NCX) blocker, antagonized the effects of both ouabain and digoxin. CTSs bind to the α subunit of pump αß protomers. Analysis of potential models suggests that, in vivo, Na+ pumps function as tetraprotomers ((αß)4) in which the binding of a single CTS to one protomer blocks all pumping activity. The paradoxical ability of digoxin-like CTSs to reactivate the ouabain-inhibited complex can be explained by de-oligomerization of the tetrameric state. The interactions between these common CTSs may be of considerable therapeutic relevance.


Asunto(s)
Señalización del Calcio/fisiología , Digoxina/administración & dosificación , Hipocampo/fisiología , Arterias Mesentéricas/fisiología , Neuronas/fisiología , Ouabaína/administración & dosificación , Vasoconstricción/fisiología , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Velocidad del Flujo Sanguíneo/fisiología , Señalización del Calcio/efectos de los fármacos , Cardiotónicos/administración & dosificación , Células Cultivadas , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas/fisiología , Hipocampo/citología , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Masculino , Arterias Mesentéricas/efectos de los fármacos , Neuronas/citología , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiología , Vasoconstricción/efectos de los fármacos
8.
Nephrol Dial Transplant ; 29(9): 1696-701, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24920842

RESUMEN

BACKGROUND: Acute kidney injury (AKI) is an important complication of cardiac surgery. Recently, elevated levels of endogenous ouabain (EO), an adrenal stress hormone with haemodynamic and renal effects, have been associated with worse renal outcome after cardiac surgery. Our aim was to develop and evaluate a new risk model of AKI using simple preoperative clinical parameters and to investigate the utility of EO. METHODS: The primary outcome was AKI according to Acute Kidney Injury Network stage II or III. We selected the Northern New England Cardiovascular Disease Study Group (NNECDSG) as a reference model. We built a new internal predictive risk model considering common clinical variables (CLIN-RISK), compared this model with the NNECDSG model and determined whether the addition of preoperative plasma EO improved prediction of AKI. RESULTS: All models were tested on >800 patients admitted for elective cardiac surgery in our hospital. Seventy-nine patients developed AKI (9.9%). Preoperative EO levels were strongly associated with the incidence of AKI and clinical complication (total ICU stay and in-hospital mortality). The NNECDSG model was confirmed as a good predictor of AKI (AUC 0.74, comparable to the NNECDSG reference population). Our CLIN-RISK model had improved predictive power for AKI (AUC 0.79, CI 95% 0.73-0.84). Furthermore, addition of preoperative EO levels to both clinical models improved AUC to 0.79 and to 0.83, respectively (ΔAUC +0.05 and +0.04, respectively, P < 0.01). CONCLUSION: In a population where the predictive power of the NNECDSG model was confirmed, CLIN-RISK was more powerful. Both clinical models were further improved by the addition of preoperative plasma EO levels. These new models provide improved predictability of the relative risk for the development of AKI following cardiac surgery and suggest that EO is a marker for renal vascular injury.


Asunto(s)
Lesión Renal Aguda/sangre , Lesión Renal Aguda/epidemiología , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Técnicas de Apoyo para la Decisión , Ouabaína/sangre , Anciano , Área Bajo la Curva , Biomarcadores/sangre , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Modelos Teóricos , Pronóstico , Medición de Riesgo , Factores de Riesgo
9.
Am J Physiol Cell Physiol ; 304(4): C324-33, 2013 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-23195071

RESUMEN

Cardiotonic steroids (CTS) of the strophanthus and digitalis families have opposing effects on long-term blood pressure (BP). This implies hitherto unrecognized divergent signaling pathways for these CTS. Prolonged ouabain treatment upregulates Ca(2+) entry via Na(+)/Ca(2+) exchanger-1 (NCX1) and TRPC6 gene-encoded receptor-operated channels in mesenteric artery smooth muscle cells (ASMCs) in vivo and in vitro. Here, we test the effects of digoxin on Ca(2+) entry and signaling in ASMC. In contrast to ouabain treatment, the in vivo administration of digoxin (30 µg·kg(-1)·day(-1) for 3 wk) did not raise BP and had no effect on resting cytolic free Ca(2+) concentration ([Ca(2+)](cyt)) or phenylephrine-induced Ca(2+) signals in isolated ASMCs. Expression of transporters in the α2 Na(+) pump-NCX1-TRPC6 Ca(2+) signaling pathway was not altered in arteries from digoxin-treated rats. Upregulated α2 Na(+) pumps and a phosphorylated form of the c-SRC protein kinase (pY419-Src, ~4.5-fold) were observed in ASMCs from rats treated with ouabain but not digoxin. Moreover, in primary cultured ASMCs from normal rats, treatment with digoxin (100 nM, 72 h) did not upregulate NCX1 and TRPC6 but blocked the ouabain-induced upregulation of these transporters. Pretreatment of ASMCs with the c-Src inhibitor PP2 (1 µM; 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) but not its inactive analog eliminated the effect of ouabain on NCX1 and TRPC6 expression and ATP-induced Ca(2+) entry. Thus, in contrast to ouabain, the interaction of digoxin with α2 Na(+) pumps is unable to activate c-Src phosphorylation and upregulate the downstream NCX1-TRPC6 Ca(2+) signaling pathway in ASMCs. The inability of digoxin to upregulate c-Src may underlie its inability to raise long-term BP.


Asunto(s)
Señalización del Calcio/efectos de los fármacos , Cardiotónicos/farmacología , Digoxina/farmacología , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/metabolismo , Ouabaína/farmacología , Familia-src Quinasas/metabolismo , Animales , Aorta/citología , Canales de Calcio/metabolismo , Cardiotónicos/administración & dosificación , Células Cultivadas , Digoxina/administración & dosificación , Activación Enzimática , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Masculino , Arterias Mesentéricas/citología , Miocitos del Músculo Liso/efectos de los fármacos , Nifedipino/farmacología , Ouabaína/administración & dosificación , Fosforilación , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Intercambiador de Sodio-Calcio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Canales Catiónicos TRPC/metabolismo , Familia-src Quinasas/antagonistas & inhibidores
10.
Crit Care Med ; 41(3): 744-55, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23314581

RESUMEN

OBJECTIVES: Acute kidney injury is a frequent complication of cardiac surgery and increases morbidity and mortality. As preoperative biomarkers predicting the development of acute kidney injury are not available, we have tested the hypothesis that preoperative plasma levels of endogenous ouabain may function as this type of biomarker. RATIONALE AND DESIGN: Endogenous ouabain is an adrenal stress hormone associated with adverse cardiovascular outcomes. Its involvement in acute kidney injury is unknown. With studies in patients and animal settings, including isolated podocytes, we tested the above mentioned hypothesis. PATIENTS: Preoperative endogenous ouabain was measured in 407 patients admitted for elective cardiac surgery and in a validation population of 219 other patients. We also studied the effect of prolonged elevations of circulating exogenous ouabain on renal parameters in rats and the influence of ouabain on podocyte proteins both "in vivo" and "in vitro." MAIN RESULTS: In the first group of patients, acute kidney injury (2.8%, 8.3%, 20.3%, p < 0.001) and ICU stay (1.4±0.38, 1.7±0.41, 2.4±0.59 days, p = 0.014) increased with each incremental preoperative endogenous ouabain tertile. In a linear regression analysis, the circulating endogenous ouabain value before surgery was the strongest predictor of acute kidney injury. In the validation cohort, acute kidney injury (0%, 5.9%, 8.2%, p < 0.0001) and ICU stay (1.2±0.09, 1.4±0.23, 2.2±0.77 days, p = 0.003) increased with the preoperative endogenous ouabain tertile. Values for preoperative endogenous ouabain significantly improved (area under curve: 0.85) risk prediction over the clinical score alone as measured by integrate discrimination improvement and net reclassification improvement. Finally, in the rat model, elevated circulating ouabain reduced creatinine clearance (-18%, p < 0.05), increased urinary protein excretion (+ 54%, p < 0.05), and reduced expression of podocyte nephrin (-29%, p < 0.01). This last finding was replicated ex vivo by incubating podocyte primary cell cultures with low-dose ouabain. CONCLUSIONS: Preoperative plasma endogenous ouabain levels are powerful biomarkers of acute kidney injury and postoperative complications and may be a direct cause of podocyte damage.


Asunto(s)
Lesión Renal Aguda/etiología , Puente de Arteria Coronaria , Válvulas Cardíacas/cirugía , Ouabaína/sangre , Lesión Renal Aguda/diagnóstico , Adulto , Anciano , Animales , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Animales , Complicaciones Posoperatorias/diagnóstico , Valor Predictivo de las Pruebas , Periodo Preoperatorio , Estudios Prospectivos , Ratas , Ratas Sprague-Dawley
11.
Curr Opin Nephrol Hypertens ; 22(1): 51-8, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23207724

RESUMEN

PURPOSE OF REVIEW: Endogenous cardiotonic steroids (CTS) exert long-term effects on salt and blood pressure homeostasis. Here we discuss recent observations on mechanisms of salt sensitivity that involve endogenous ouabain and novel pathways in the brain and discuss their possible relationship to arterial and renal function in hypertension. RECENT FINDINGS: Chronic elevation of brain sodium promotes sustained hypertension mediated by central endogenous ouabain and the Na(+) pump α-2 catalytic subunit. The intermediary pressor mechanism in the brain involves aldosterone biosynthesis, activation of mineralocorticoid receptors and increased epithelial sodium channel activity. In the periphery, elevated plasma CTS raise contractility and blood pressure by augmentation of sympathetic nerve responses, increasing arterial Ca(2+) signaling and blunting nitric oxide production in the renal medulla and collecting ducts. SUMMARY: Endogenous ouabain in the brain appears to play a critical role in salt sensitivity and hypertension. In the periphery, the J-shaped relationship of plasma endogenous ouabain in response to short-term changes in salt balance in humans raises the possibility that endogenous ouabain contributes to the increased risk of adverse cardiovascular events associated with both low and high salt intakes.


Asunto(s)
Presión Sanguínea , Homeostasis/fisiología , Hipertensión/metabolismo , Ouabaína/metabolismo , Cloruro de Sodio/metabolismo , Animales , Encéfalo/metabolismo , Humanos , Hipertensión/fisiopatología , Cloruro de Sodio/efectos adversos
12.
Adv Exp Med Biol ; 961: 365-74, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23224895

RESUMEN

Arterial smooth muscle (ASM) Na(+)/Ca(2+) exchanger type 1 (NCX1) and TRPC/Orai-containing receptor/store-operated cation channels (ROC/SOC) are clustered with α2 Na(+) pumps in plasma membrane microdomains adjacent to the underlying junctional sarcoplasmic reticulum. This arrangement enables these transport proteins to function as integrated units to help regulate local Na(+) metabolism, Ca(2+) signaling, and arterial tone. They thus influence vascular resistance and blood pressure (BP). For instance, upregulation of NCX1 and TRPC6 has been implicated in the pathogenesis of high BP in several models of essential hypertension. The models include ouabain-induced hypertensive rats, Milan hypertensive rats, and Dahl salt-sensitive hypertensive rats, all of which exhibit elevated plasma ouabain levels. We suggest that these molecular mechanisms are key contributors to the increased vascular resistance ("whole body autoregulation") that elevates BP in essential hypertension. Enhanced expression and function of ASM NCX1 and TRPC/Orai1-containing channels in hypertension implies that these proteins are potential targets for pharmacological intervention.


Asunto(s)
Señalización del Calcio , Hipertensión/metabolismo , Proteínas Musculares/metabolismo , Músculo Liso Vascular/metabolismo , Intercambiador de Sodio-Calcio/metabolismo , Canales Catiónicos TRPC/metabolismo , Animales , Calcio/metabolismo , Modelos Animales de Enfermedad , Humanos , Hipertensión/genética , Hipertensión/patología , Proteínas Musculares/genética , Músculo Liso Vascular/patología , Ratas , Ratas Endogámicas Dahl , Sodio/metabolismo , Intercambiador de Sodio-Calcio/genética , Canales Catiónicos TRPC/genética , Canal Catiónico TRPC6
13.
Am J Physiol Heart Circ Physiol ; 302(6): H1317-29, 2012 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-22245773

RESUMEN

Endogenous cardiotonic steroids (CTS) raise blood pressure (BP) via vascular sodium calcium exchange (NCX1.3) and transient receptor-operated channels (TRPCs). Circulating CTS are superelevated in pregnancy-induced hypertension and preeclampsia. However, their significance in normal pregnancy, where BP is low, is paradoxical. Here we test the hypothesis that vascular resistance to endogenous ouabain (EO) develops in normal pregnancy and is mediated by reduced expression of NCX1.3 and TRPCs. We determined plasma and adrenal levels of EO and the impact of exogenous ouabain in pregnancy on arterial expression of Na(+) pumps, NCX1.3, TRPC3, and TRPC6 and BP. Pregnant (embryonic day 4) and nonpregnant rats received infusions of ouabain or vehicle. At 14-16 days, tissues and plasma were collected for blotting and EO assay by radioimmunoassay (RIA), liquid chromatography (LC)-RIA, and LC-multidimensional mass spectrometry (MS3). BP (-8 mmHg; P < 0.05) and NCX1.3 expression fell (aorta -60% and mesenteric artery -30%; P < 0.001) in pregnancy while TRPC expression was unchanged. Circulating EO increased (1.14 ± 0.13 nM) vs. nonpregnant (0.6 ± 0.08 nM; P < 0.05) and was confirmed by LC-MS3 and LC-RIA. LC-MS3 revealed two previously unknown isomers of EO; one increased ∼90-fold in pregnancy. Adrenal EO but not isomers were increased in pregnancy. In nonpregnant rats, similar infusions of ouabain raised BP (+24 ± 3 mmHg; P < 0.001). In ouabain-infused rats, impaired fetal and placental growth occurred with no BP increase. In summary, normal pregnancy is an ouabain-resistant state associated with low BP, elevated circulating levels of EO, two novel steroidal EO isomers, and increased adrenal mass and EO content. Ouabain raises BP only in nonpregnant animals. Vascular resistance to the chronic pressor activity of endogenous and exogenous ouabain is mediated by suppressed NCX1.3 and reduced sensitivity of events downstream of Ca(2+) entry. The mechanisms of EO resistance and the impaired fetal and placental growth due to elevated ouabain may be important in pregnancy-induced hypertension (PIH) and preeclampsia (PE).


Asunto(s)
Arterias/efectos de los fármacos , Arterias/metabolismo , Presión Sanguínea/efectos de los fármacos , Cardiotónicos/administración & dosificación , Resistencia a Medicamentos , Ouabaína/administración & dosificación , Intercambiador de Sodio-Calcio/metabolismo , Glándulas Suprarrenales/metabolismo , Animales , Calcio/metabolismo , Cardenólidos/sangre , Cardenólidos/metabolismo , Cardiotónicos/toxicidad , Cromatografía Liquida , Regulación hacia Abajo , Femenino , Retardo del Crecimiento Fetal/inducido químicamente , Homeostasis , Infusiones Subcutáneas , Espectrometría de Masas , Ouabaína/toxicidad , Péptidos Cíclicos , Placenta/efectos de los fármacos , Placentación , Embarazo , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Saponinas/sangre , Saponinas/metabolismo , Canales Catiónicos TRPC/metabolismo , Factores de Tiempo , Regulación hacia Arriba
14.
Am J Physiol Heart Circ Physiol ; 302(3): H611-20, 2012 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-22140038

RESUMEN

The Milan hypertensive strain (MHS) rats are a genetic model of hypertension with adducin gene polymorphisms linked to enhanced renal tubular Na(+) reabsorption. Recently we demonstrated that Ca(2+) signaling is augmented in freshly isolated mesenteric artery myocytes from MHS rats. This is associated with greatly enhanced expression of Na(+)/Ca(2+) exchanger-1 (NCX1), C-type transient receptor potential (TRPC6) protein, and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2) compared with arteries from Milan normotensive strain (MNS) rats. Here, we test the hypothesis that the enhanced Ca(2+) signaling in MHS arterial smooth muscle is directly reflected in augmented vasoconstriction [myogenic and phenylephrine (PE)-evoked responses] in isolated mesenteric small arteries. Systolic blood pressure was higher in MHS (145 ± 1 mmHg) than in MNS (112 ± 1 mmHg; P < 0.001; n = 16 each) rats. Pressurized mesenteric resistance arteries from MHS rats had significantly augmented myogenic tone and reactivity and enhanced constriction to low-dose (1-100 nM) PE. Isolated MHS arterial myocytes exhibited approximately twofold increased peak Ca(2+) signals in response to 5 µM PE or ATP in the absence and presence of extracellular Ca(2+). These augmented responses are consistent with increased vasoconstrictor-evoked sarcoplasmic reticulum (SR) Ca(2+) release and increased Ca(2+) entry, respectively. The increased SR Ca(2+) release correlates with a doubling of inositol 1,4,5-trisphosphate receptor type 1 and tripling of SERCA2 expression. Pressurized MHS arteries also exhibited a ∼70% increase in 100 nM ouabain-induced vasoconstriction compared with MNS arteries. These functional alterations reveal that, in a genetic model of hypertension linked to renal dysfunction, multiple mechanisms within the arterial myocytes contribute to enhanced Ca(2+) signaling and myogenic and vasoconstrictor-induced arterial constriction. MHS rats have elevated plasma levels of endogenous ouabain, which may initiate the protein upregulation and enhanced Ca(2+) signaling. These molecular and functional changes provide a mechanism for the increased peripheral vascular resistance (whole body autoregulation) that underlies the sustained hypertension.


Asunto(s)
Señalización del Calcio/fisiología , Hipertensión Renal/metabolismo , Arteria Mesentérica Superior/metabolismo , Músculo Liso Vascular/metabolismo , Vasoconstricción/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Hipertensión Renal/genética , Hipertensión Renal/fisiopatología , Arteria Mesentérica Superior/citología , Arteria Mesentérica Superior/efectos de los fármacos , Músculo Liso Vascular/citología , Ouabaína/farmacología , Ratas , Ratas Mutantes , Retículo Sarcoplasmático/metabolismo , Cloruro de Sodio Dietético/farmacología , España , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiología , Vasoconstricción/efectos de los fármacos
15.
Am J Physiol Heart Circ Physiol ; 302(5): H1031-49, 2012 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-22058154

RESUMEN

Excess dietary salt is a major cause of hypertension. Nevertheless, the specific mechanisms by which salt increases arterial constriction and peripheral vascular resistance, and thereby raises blood pressure (BP), are poorly understood. Here we summarize recent evidence that defines specific molecular links between Na(+) and the elevated vascular resistance that directly produces high BP. In this new paradigm, high dietary salt raises cerebrospinal fluid [Na(+)]. This leads, via the Na(+)-sensing circumventricular organs of the brain, to increased sympathetic nerve activity (SNA), a major trigger of vasoconstriction. Plasma levels of endogenous ouabain (EO), the Na(+) pump ligand, also become elevated. Remarkably, high cerebrospinal fluid [Na(+)]-evoked, locally secreted (hypothalamic) EO participates in a pathway that mediates the sustained increase in SNA. This hypothalamic signaling chain includes aldosterone, epithelial Na(+) channels, EO, ouabain-sensitive α(2) Na(+) pumps, and angiotensin II (ANG II). The EO increases (e.g.) hypothalamic ANG-II type-1 receptor and NADPH oxidase and decreases neuronal nitric oxide synthase protein expression. The aldosterone-epithelial Na(+) channel-EO-α(2) Na(+) pump-ANG-II pathway modulates the activity of brain cardiovascular control centers that regulate the BP set point and induce sustained changes in SNA. In the periphery, the EO secreted by the adrenal cortex directly enhances vasoconstriction via an EO-α(2) Na(+) pump-Na(+)/Ca(2+) exchanger-Ca(2+) signaling pathway. Circulating EO also activates an EO-α(2) Na(+) pump-Src kinase signaling cascade. This increases the expression of the Na(+)/Ca(2+) exchanger-transient receptor potential cation channel Ca(2+) signaling pathway in arterial smooth muscle but decreases the expression of endothelial vasodilator mechanisms. Additionally, EO is a growth factor and may directly participate in the arterial structural remodeling and lumen narrowing that is frequently observed in established hypertension. These several central and peripheral mechanisms are coordinated, in part by EO, to effect and maintain the salt-induced elevation of BP.


Asunto(s)
Hipertensión/inducido químicamente , Cloruro de Sodio Dietético/efectos adversos , Animales , Cardiotónicos/farmacología , Femenino , Humanos , Hipotálamo/efectos de los fármacos , Hipotálamo/fisiopatología , Masculino , Ratones , Ouabaína/sangre , Ouabaína/farmacología , Embarazo , Ratas , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología
16.
Psychiatry Res ; 309: 114399, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35078006

RESUMEN

Endogenously produced cardiac glycosides, like endogenous ouabain (EO), are putative hormones that have been implicated in the pathophysiology of bipolar disorder. Individuals with bipolar disorder appear to be unable to sufficiently upregulate production of EO in situations of increased need. This study was performed to determine the effect of sleep deprivation on the circulating levels of EO. Plasma EO concentrations were measured by ouabain-radioimmunoassay in heterozygote Na,K-ATPase a2 knockout (KO) mice, which have been used as an animal model of mania, and wildtype siblings at baseline and after sleep fragmentation utilizing the moving bar method. a2 KO animals had elevated endogenous ouabain concentrations compared to wild type controls (0.82 ± SD 0.22 nM vs 0.26 ± 0.02, P = 0.03). Sleep fragmentation increased ouabain concentrations in wild type mice (0.53 ± 0.08 nM sleep fragmentation vs 0.26 ± 0.02 nM baseline, P = 0.04), but not in a2 KO mice (0.60 ± 0.07 nM sleep fragmentation vs 0.82 ± 0.22 nM baseline, P > 0.05). These studies demonstrate that sleep disturbance can increase EO in control mice but animals that exhibit some manic behaviors are unable to increase EO production.


Asunto(s)
Trastorno Bipolar , Hipertensión , Animales , Humanos , Ratones , Ouabaína , Privación de Sueño , ATPasa Intercambiadora de Sodio-Potasio/metabolismo
17.
J Hypertens ; 40(8): 1504-1512, 2022 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-35881450

RESUMEN

OBJECTIVE: Salt sensitivity is a powerful risk factor for cardiovascular (CV) disease and mortality in both normotensive and hypertensive patients. We investigated the predictive value of the salt sensitivity phenotype in the development of CV events and hypertensive target organ damage (TOD) among essential hypertensive patients. METHODS: Eight hundred forty-four naive hypertensive patients were recruited and underwent an acute saline test during which blood pressure (BP) displayed either no substantial variation (salt-resistant, SR individuals), an increase (salt-sensitive, SS), or a paradoxical decrease (inverse salt-sensitive, ISS). Sixty-one patients with the longest monitored follow-up (median 16 years) for blood pressure and organ damage were selected for the present study. A clinical score for TOD development based on the severity and the age of onset was set up by considering hypertensive heart disease, cerebrovascular damage, microalbuminuria, and vascular events. RESULTS: CV events were significantly higher among SS and ISS than in SR patients. The relative risk of developing CV events was 12.67 times higher in SS than SR and 5.94 times higher in ISS than SR patients. The development of moderate to severe TOD was 10-fold higher in SS and over 15-fold higher in ISS than in SR patients. Among the three phenotypes, changes in plasma endogenous ouabain were linked with the blood pressure effects of saline. CONCLUSIONS: Salt sensitivity and inverse salt sensitivity appear to be equivalent risk factors for CV events. The response to an acute saline test is predictive of CV damage for newly identified ISS individuals.


Asunto(s)
Enfermedades Cardiovasculares , Hipertensión , Presión Sanguínea , Hipertensión Esencial/complicaciones , Humanos , Hipertensión/etiología , Factores de Riesgo , Cloruro de Sodio/farmacología , Cloruro de Sodio Dietético/efectos adversos
18.
Biochim Biophys Acta ; 1802(12): 1219-29, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20211726

RESUMEN

Salt retention as a result of chronic, excessive dietary salt intake, is widely accepted as one of the most common causes of hypertension. In a small minority of cases, enhanced Na(+) reabsorption by the kidney can be traced to specific genetic defects of salt transport, or pathological conditions of the kidney, adrenal cortex, or pituitary. Far more frequently, however, salt retention may be the result of minor renal injury or small genetic variation in renal salt transport mechanisms. How salt retention actually leads to the increase in peripheral vascular resistance (the hallmark of hypertension) and the elevation of blood pressure remains an enigma. Here we review the evidence that endogenous ouabain (an adrenocortical hormone), arterial smooth muscle α2 Na(+) pumps, type-1 Na/Ca exchangers, and receptor- and store-operated Ca(2+) channels play key roles in the pathway that links salt to hypertension. We discuss cardenolide structure-function relationships in an effort to understand why prolonged administration of ouabain, but not digoxin, induces hypertension, and why digoxin is actually anti-hypertensive. Finally, we summarize recent observations which indicate that ouabain upregulates arterial myocyte Ca(2+) signaling mechanisms that promote vasoconstriction, while simultaneously downregulating endothelial vasodilator mechanisms. In sum, the reports reviewed here provide novel insight into the molecular mechanisms by which salt retention leads to hypertension.


Asunto(s)
Hipertensión/metabolismo , Ouabaína/metabolismo , Intercambiador de Sodio-Calcio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Sodio/metabolismo , Canales Catiónicos TRPC/metabolismo , Corteza Suprarrenal/metabolismo , Corteza Suprarrenal/patología , Corteza Suprarrenal/fisiopatología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/genética , Cardiotónicos/farmacología , Digoxina/uso terapéutico , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Hipertensión/patología , Hipertensión/fisiopatología , Transporte Iónico/efectos de los fármacos , Transporte Iónico/genética , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Hipófisis/metabolismo , Hipófisis/patología , Hipófisis/fisiopatología , Intercambiador de Sodio-Calcio/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , Relación Estructura-Actividad , Canales Catiónicos TRPC/genética
19.
Biochim Biophys Acta ; 1802(12): 1214-8, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20226856

RESUMEN

The Na(+) pump and its Endogenous modulator Ouabain (EO) can be considered as an ancestral enzymatic system, conserved among species ranging from Drosophila to humans, related to Na handling. In this review, we examine how EO is linked with vascular function in hypertension and if it impacts the pathogenesis of heart and renal failure. Moreover, the molecular mechanism of endogenous ouabain-linked hypertension involves the sodium pump/sodium-calcium exchanger duet. Biosynthesis of EO occurs in adrenal glands and is under the control of angiotensin II, ACTH and epinephrine. Elevated concentrations of EO and in the sub-nanomolar concentration range were found to stimulate proliferation and differentiation of cardiac and smooth muscle cells. They may have a primary role in the development of cardiac dysfunction and failure. Experimental data suggest that the Na/K-ATPase α(2)-catalytic subunit causes EO-induced vasoconstriction. Finally, maneuvers that promote Na depletion, as diuretic therapy or reduced Na intake, raise the EO levels. Taken together, these findings suggest a key role for EO in body Na homeostasis.


Asunto(s)
Insuficiencia Cardíaca/metabolismo , Riñón/metabolismo , Ouabaína/metabolismo , Insuficiencia Renal/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Sodio/metabolismo , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/patología , Angiotensina II/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Diuréticos/uso terapéutico , Drosophila , Epinefrina/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Homeostasis/efectos de los fármacos , Humanos , Hipertensión , Riñón/patología , Riñón/fisiopatología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Insuficiencia Renal/tratamiento farmacológico , Insuficiencia Renal/patología , Insuficiencia Renal/fisiopatología , Intercambiador de Sodio-Calcio , Vasoconstricción/efectos de los fármacos
20.
Curr Hypertens Rep ; 13(1): 14-20, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20972650

RESUMEN

The sodium pump, an ancestral enzyme with conserved ability to bind ouabain, plays a key role in salt conservation and is regulated by aldosterone and endogenous ouabain (EO). Plasma EO is elevated in about 45% of patients with essential hypertension and correlates with blood pressure. The relationship of EO with Na(+) balance is complex. Na(+) depletion raises circulating EO, whereas acute saline loads have no effect on EO in essential hypertension, and ambient levels of EO are unrelated to the saline sensitivity of blood pressure. Short-term periods of high dietary salt elevate EO and the relationship with salt balance in normal individuals is V-shaped, whereas the long-term relationship is likely to be L-shaped. Normal individuals suppress the high EO transient triggered by high-salt diets and avoid hypertension. In contrast, patients with elevated EO on normal Na(+) intakes have hypertension related to poor modulation of EO biosynthesis, clearance, or both.


Asunto(s)
Aldosterona/sangre , Hipertensión/inducido químicamente , Ouabaína/sangre , Receptores de Superficie Celular , Sodio en la Dieta/efectos adversos , ATPasa Intercambiadora de Sodio-Potasio/sangre , Dieta , Humanos , Hipertensión/patología , Estado Nutricional , Factores de Riesgo , Sodio en la Dieta/sangre , Sodio en la Dieta/metabolismo
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